Antibiotics of cephalosporin series are widely used in therapy for treatment of diseases which are caused by general pathogenic bacteria in human beings and animals. It has been known that such antibiotics are useful for the treatment of diseases caused by bacteria exhibiting the resistance to other antibiotics, e.g. penicillin-resistant bacteria, and for treatment of penicillin-sensitive patients.
In most circumstances it is desirable to employ antibiotics showing broad antibacterial activities against both Gram-positive and Gram-negative bacteria. In this regard, there have been made many studies in developing a variety of cephalosporin antibiotics with broad-spectrum antibiotic activities.
For example, in GB patent No. 1,399,086 there are disclosed many cephalosporin derivatives which are shown by the formula ##STR2## wherein R is hydrogen or an organic group;
R.sup.a is an etherifying monovalent organic group linked to the oxygen atom through a carbon atom; PA1 B is --S-- or ##STR3## and P is an organic group. PA1 R" is a C.sub.1.about.4 alkyl, C.sub.3.about.7 cycloalkyl, furylmethyl or thienylmethyl group; and PA1 R'" is hydrogen or a carbamoyl, carboxymethyl, sulfonyl or methyl group. PA1 R.sup.2 is hydrogen, acyl, substituted or unsubstituted aryl, substituted alkyl, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, cycloalkenyl, or O- or S-containing 5-membered hetero cyclic group; PA1 R.sup.3 hydrogen or alkyl; PA1 R.sup.4 is an acyloxyalkyl, acylthioalkyl, substituted or unsubstituted pyridiniumalkyl, substituted or unsubstituted heterocyclic thioalkyl, alkyl, hydroxy, or substituted or unsubstituted thiazoliumalkyl group, or halogen; PA1 R.sup.5 is carboxy or a protected carboxy group, wherein R.sup.5 is COO.sup.- when R.sup.4 is a substituted or unsubstituted pyridiniumalkyl group or a substituted or unsubstituted thiazoliumalkyl group; and PA1 the dotted line "- - - " represents a single bond or a double bond. PA1 R.sup.2 is a substituted or unsubstituted lower aliphatic hydrocarbon group, or a cycloalkenyl group; and ##STR7## is a substituted or unsubstituted heterocyclic cation group containing one or more nitrogen atoms; ##STR8## wherein R.sup.1 and R.sup.2 are the same as defined in the formula(D), respectively; PA1 R.sup.4 is a protected carboxyl group; and PA1 X.sup.- is an acid residue. PA1 R.sup.2 is a protected or unprotected lower aliphatic hydrocarbon group, cyclo(lower)alkyl, or cyclo(lower)alkenyl group; PA1 R.sup.3 is (lower)alkylamino, N-protected(lower)alkylamino, di(lower) alkylamino, sulfo(lower)alkylamino, hydroxy(lower)alkylamino, N-protected hydroxy(lower)alkylamino, acyloxy(lower)alkyl, (lower)alkoxy(lower)alkoxy(lower)alkyl, di(lower)alkylamino (lower)alkyl, (lower)alkylthio(lower)alkyl, (lower)alkylthio, (lower)alkoxy(lower)alkoxy, (lower)alkoxy, hydroxy(lower)alkoxy, acyl(lower)alkyl, hydroxy(lower)alkylthio, di(lower)alkylamino (lower)alkylthio, N-containing unsaturated 5-membered heterocyclic group, N-containing unsaturated 5-membered heterocyclic thio group, or N-containing unsaturated 5- or 6-membered heterocyclic (lower)alkyl group which may be optionally substituted with suitable substituent(s); and PA1 R.sup.4 is hydrogen or a (lower)alkyl group. PA1 Am is amino or a substituted amino group; PA1 T is a thiadiazoly moiety, where one carbon atom is bonded to Am and the other carbon atom is bonded to the group of --C(.dbd.N--O--R.sup.2)--; PA1 R.sup.2 is hydrogen, a substituted or unsubstituted carbamoyl group, a cycloalkyl group, or a substituted or unsubstituted carbamoyl group; and PA1 R.sup.1 is a substituted or unsubstituted thiazolium group, a substituted or unsubstituted pyrazolium group, a tri(lower)alkyl ammonium group or a pyridinium group of the following formula ##STR11## [wherein R.sup.a is (lower)alkyl [which is substituted with a substituent selected from the group consisting of cycloalkyl, methyl, hydroxy, alkoxy, halogen, cyano, carbamoyl, carboxyl and sulfonyl], (lower)alkenyl or carboxy-substituted (lower)alkenyl, (lower)alkylthio or carboxy-substituted (lower)alkylthio, amino or mono-substituted amino [wherein the substituent is selected from the group consisting of (lower) alkyl, (lower)alkanoyl or aminobenzenesulfonyl], di(lower)alkylamino, carbamoyl [which is substituted by (lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy, hydroxy or cyano], di(lower)alkylcarbamoyl, thiocarbamoyl, cycloalkyl, phenyl, hydroxy, (lower)alkoxy, halogen, (lower)alkoxycarbonyl, (lower)alkanoyloxy, (lower)alkanoyl, carboxy, sulfocyano, nitro, a hydroxysulfo(lower)alkyl group]; PA1 R.sup.b is hydrogen, a carbamoyl group, or a group selected from the groups defined for the R.sup.a ; and PA1 R.sup.c is hydrogen or a group selected from the groups as defined in the R.sup.a. PA1 R.sup.2 is a C.sub.1.about.4 alkyl (preferably a straight alkyl group such as methyl, ethyl, n-propyl or n-butyl), C.sub.3.about.4 alkenyl (preferably allyl), C.sub.3.about.7 cycloalkyl, substituted or unsubstituted amino or substituted or unsubstituted phenyl (preferably phenyl, 4-hydroxyphenyl, 4-chlorophenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl or 2,6-dimethyoxyphenyl) group; PA1 R.sup.3 is hydrogen or a C.sub.1.about.4 alkyl group(preferably methyl or ethyl); and PA1 Q is N or CH. PA1 n is an integer of 0 or 1; PA1 R.sup.4 is hydrogen or an amino protecting group; PA1 R.sup.5 is a C.sub.1.about.4 alkyl, C.sub.3.about.4 alkenyl or C.sub.3.about.4 alkynl group, or --C(R.sup.a)(R.sup.b)CO.sub.2 (R.sup.c) wherein R.sup.a and R.sup.b same or different are a hydrogen atom or a C.sub.1.about.4 alkyl group, or R.sup.a and R.sup.b may form a C.sub.3.about.7 cycloalkyl group with the carbon atom to which they are linked; and R.sup.c is hydrogen or a carboxyl protecting group; PA1 R.sup.5 is a hydrogen atom or a carboxyl protecting group; and PA1 L is a leaving group.
After the invention of these compounds, there were many attempts to develop antibiotic compounds having more improved properties, to a certain bacteria especially to Gram-negative bacteria.
GB patent No. 1,522,140 discloses cephalosporin antibiotic compounds of the formula(B) which exist as syn isomers, or as a mixture of syn and anti isomers wherein the syn isomers are present in at least 90%, ##STR4## wherein R' is a furyl or thienyl group;
The foregoing cephalosporin compounds have high antibacterial activities against a range of Gram-positive and Gram-negative bacteria, and particularly high stability to .beta.-lactamases produced by various Gram-negative bacteria. Moreover, they are very stable in vivo.
Recently, there have been efforts to prepare new antibiotics having more improved and broadened antibiotic spectrum and while showing potent antibiotic activities, especially against Gram-negative bacteria. Consequently a large number of cephalosporin antibiotics with analogous structures to those above, have been developed.
As a part of said efforts, an acylamido group has been introduced into the 7-position of the cephem nucleus as shown in the foregoing formula(B) and a certain groups have been introduced into the 3-position thereof.
For example, in BE patent No. 852,427 there are reported a number of cephalosporin compounds having antibiotic activities which are shown by the foregoing formula(A) wherein the R is substituted with various organic groups including 2-aminothiazol, the oxygen atom of the oxyimino group, is directly bonded to an aliphatic hydrocarbon group, and which aliphatic hydrocarbon group may be itself substituted with a carboxy group. The substituent in 3-position of such compounds is an acetoxymethyl, hydroxymethyl, formyl group, or an optionally substituted hetero cyclic thiomethyl group.
Also, in U.S. Pat. No. 4,390,534 to Psutomu Terachi et al, there are reproted new cephem compounds of the formula ##STR5## wherein R.sup.1 is amino or a protected amino group;
While the P of the aforesaid GB patent No. 1,399,086 or the R.sup.4 of the aforesaid U.S. Pat. No. 4,390,534 are defined very broadly as an organic group or a substituted or unsubstituted heterocyclic thioalkyl group, respectively, there is not therein mentioned the heart of the present invention that is a compound having a (1-substituted-4,6-diaminopyrimidinium-2-yl) thiomethyl group introduced into 3-position of the cephem nucleus.
Also, European patent application No. 62,321 discloses cephem compounds of the formula(D) and pharmaceutically acceptable salts thereof, and their intermediates of the formula(D') ##STR6## wherein R.sup.1 is amino or a protected amino group;
In European patent application NO. 74,563, the cephem compounds of the formula(E) and their salts are proposed as antibiotic compounds ##STR9## wherein R.sup.1 is amino or a protected amino group;
There are disclosed cephem compounds of the formula(F) and their salts in European patent application No. 47,977 ##STR10## wherein n is an integer of 0 or 1;
As described above, there are a variety of cephem compounds whose 7-positions are substituted by a substituted aminothiadiazole ring. However, there are no reports about the most important characteristic of the present invention that is a (1-substituted-4,6-diaminopyrimidinium-2-yl)thiomethyl group is introduced into the 3-position of the cephem nucleus.